Trial of 5-Fluorouracil (5FU)-Based Therapy in Combination With Fruquintinib in Patients With Locally Advanced Unresectable or Metastatic Colorectal Cancer

Inclusion Criteria: 1. Male or female ≥18 years of age. 2. Written informed consent is required before performing any trial-specific tests or procedures. Signing of the informed consent form can occur outside the 28-day screening period. 3. Histopathologically or cytologically confirmed locally advanced unresectable or metastatic colorectal cancer. The study will include an all-comer population, meaning that patients will not be excluded based on specific molecular markers such as microsatellite instability-high (MSI-H) or B-Raf proto-oncogene mutations (BRAF mutations). However, as part of the Standard of Care, comprehensive molecular testing will be performed to assess MSI status, and other relevant biomarkers. For patients with MSI-H or BRAF mutations confirmed, treatment may be adjusted per Standard of Care practices. 4. Measurable disease per RECISTv1.1. 5. No prior systemic treatment. Patients with resected disease who later develop unresectable recurrence without prior systemic therapy remain eligible. 6. ECOG performance status of 0 or 1. 7. Life expectancy ≥6 months per treating physician's assessment. 8. Patients of childbearing potential must agree to use an adequate method of contraception during the study and for 30 days after the last dose of study treatment. 9. Patients must be able to swallow oral tablets. Exclusion Criteria: 1. Hematology laboratory values of: 1. Absolute neutrophil count ≤1500 cells/mm3 2. Platelets ≤100,000 cells/mm3 3. Hemoglobin ≤9 g/dL 4. White blood count ≤3000 cells/mm3. 2. Hepatic laboratory values of aspartate transaminase (AST) or alanine aminotransferase (ALT): 1. \>5 × upper limits of normal (ULN) if the documented history of hepatic metastases; or 2. \>2.5 × ULN if no liver metastases are present. 3. Serum albumin \<2.8 g/dL. 4. Total bilirubin \>1.7 mg/dL × ULN. 5. Prothrombin time (PT) or international normalized ratio (INR) \>1.5 × ULN. Note: Patients receiving therapeutic doses of anticoagulant therapy may be considered eligible if PT and INR are within the acceptable institutional therapeutic limits. 6. Serum creatinine or serum urea \>1.5 × ULN. 7. Estimated glomerular filtration rate \<50 mL/min. 8. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level. 9. Positive pregnancy test, pregnant, or breastfeeding for all women of child-bearing potential. 10. Per treating physician's assessment, any other clinically significant laboratory abnormality that would compromise patient safety or the outcome of the study. 11. Any clinically significant and/or uncontrolled cardiac-related abnormality that would compromise patient safety or the outcome of the study including, but not limited to: 1. Arrhythmia 2. Bradycardia 3. Tachycardia 4. Symptomatic valvular disease 5. Symptomatic congestive heart failure is classified by the New York Heart Association as Class III or IV 6. Unstable angina pectoris. 12. Myocardial infarction within the past 6 months from consent. 13. Active bleeding diathesis. 14. Current complaints of persistent constipation or history of chronic constipation, untreatable bowel obstruction, or fecaloma within the past 6 months from consent. 15. Receiving chronic treatment with corticosteroids ≥5 mg of prednisone per day (or equivalent) or other systemic immunosuppressive agents. Topical or nasal corticosteroids are allowed. 16. Known history and/or uncontrolled hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV)-1 or HIV-2. 17. History of galactose intolerance, deficiency of Lapp lactase, or glucose-galactose malabsorption. 18. History of malignancy or active treatment for malignancy other than CRC (i.e., radiation or chemotherapy, including monoclonal antibodies) within 5 years. Note: Patients with squamous or basal cell carcinomas of the skin, carcinomas in situ of the cervix or uterus, ductal breast cancer in situ, resected low-grade prostate cancer, or other malignancies that in the opinion of the investigator are considered cured may participate. 19. Receipt of live, attenuated vaccine (e.g., intranasal influenza, measles, mumps, rubella, varicella) or close contact with someone who has received a live, attenuated vaccine within the past 1 month from consent. Note: Influenza vaccine will be allowed if administered \>21 days. 20. Receipt of any investigational agent or study treatment within the past 30 days from consent for a condition other than CRC. 21. Receipt of any protein or antibody-based therapeutic agents (e.g., growth hormones or monoclonal antibodies) within the past 3 months from consent for a condition other than CRC. 22. Uncontrolled hypertension 23. Active infection requiring treatment 24. Recent history of major surgery 25. Thromboembolic events during the past 6 months 26. Adults unable to consent 27. Prisoners